Multiple myeloma is characterized by infiltration of malignant plasma cells into the bone marrow and which accounts for ~1% of all malignancies and >10% of malignant hematological neoplasms. Despite recent advances in conventional and high-dose chemotherapies, MM remains essentially incurable. An important signaling pathway in MM is the PI3K/AKT/mTOR signaling pathway. The main objective of this project is to provide a rationale for the use of mTOR inhibitors as a chemotherapeutic target against multiple myeloma. The aims include using physiologically relevant disseminated bone marrow xenograft models to study the role of VEGF and angiogenesis on the growth and survival of tumors treated with mTOR inhibitors. In addition, the ability of hyperactive AKT to regulate VEGF internal ribosome entry site (IRES) function in sensitizing MM cells to hypoxia and apoptosis induced by rapalogs will be tested. The identification and characterization of IRES-trans activating factors (ITAFs) that regulate sensitivity to mTOR inhibitors will also be attempted. These specific aims build upon the foundation of our previous work studying the anti-myeloma effects of mTOR inhibitors and will advance our understanding of AKT's regulatory role on the IRES-mediated fail safe protein translation pathway. These studies are significant because they bone marrow niche provides pro-survival and pro-angiogenic signals to the engrafted tumor cells that contribute to the pathology and almost universal chemotherapy resistance of this incurable disease.